Angiotensin II is a powerful vasoconstrictor agent that has been implicated as the main causative agent in the etiology of renovascular hypertension.
Angiotensin II is formed from angiotensin I by the action of angiotensin converting enzyme. Angiotensin I is a biologically inert decapeptide cleaved from the blood protein angiotensinogen by the action of the enzyme renin [O paril et al. New England J. of Med., 291, 389-401 (1974)]. Angiotensinogen and renin are also biologically inert.
Angiotensin converting enzyme is also reponsible for the inactivation of bradykinin, a vasodilator agent that has been implicated in the regulation of renal function [Erdos, Circulation Research 36, 247 (1975)].
Agents that inhibit angiotensin converting enzyme can therefore counteract the pressor effect of angiotensin I since this is due only to its conversion to angiotensin II. These agents can be used therapeutically in the treatment of forms of renovascular and malignant hypertension as well as other forms of angiotensin dependent hypertension [Gavras et al., New England J. of Med. 291, 817 (1974)].
According to Oparil et al., supra, angiotensin II has a major role in maintaining circulatory homeostasis in the sodium depleted animal, but in the normal animal on a normal salt intake, angiotensin II is not required for the acute maintenance of blood pressure. In a variety of conditions that stress the renin - angiotensin system, acute administration of an Angiotensin converting Enzyme inhibitor or an angiotensin II blocker lowers blood pressure and causes a rise in plasma renin activity.
Certain mercaptoacyl amino acids have been disclosed in the literature. U.S. Pat. No. 3,246,025, Apr. 12, 1966, shows mercaptopropionyl glycine derivatives which are useful for strengthening function of the liver and as antidotes for such poisons as mercury and organoarsenic compounds. See also German Offenlegungsschrift No. 2,349,707. U.S. Pat. No. 3,879,480, July 29, 1957, shows N-(.alpha.-mercaptoacyl)amino acids useful for prophylaxis and therapy in treating a metabolic disorder, such as nosotoxicosis due to a heavy metal, radiation disorder, diabetes or hepatitis. U.S. Pat. No. 3,857,951, Dec. 31, 1974, shows the use of 2-mercaptopropionylglycine and its alkali metal salts in treating respiratory diseases.
It has been reported that 2-mercaptopropionylglycine, known as a liver protecting agent, produced lowering of the blood pressure upon intravenous injection to anesthetized normotensive rats [Schulze, Arzneim. Forsch. 22, 1433 (1972)], an unreliable model [Schwartz, Methods in Pharmacology, Vol. 1, 125 (1971); Berger, Selected Pharmacological Testing Methods, Vol. 3, 171, 194 (1968)]; while others have reported no noticeable effects on blood pressure, etc., [Fujimura et al., Nippon Yakurigaku Zasshi 60, 278-92 (1964)]. See also Ripa, Proc. Int. Symp. Thiola, Osaka, Japan 1970, p. 226-230, who reported that in normotensive rats .alpha.-mercaptopropionylglycine increases angiotensinogen and lowers renin blood levels by a feed-back homeostatic mechanism.
A variety of dipeptides are known as shown in the text Pettit, Synthetic Peptides, Vol. 1 (1971), e.g., pages 94-104. Additionally, foodstuff additives are shown, for example, in the following U.S. Pat. Nos. 2,851,482, L-arginine-L-glutamate; 3,799,918, alkyl esters of .alpha.-aspartyl-.alpha.-alkyl aliphatic amino acid dipeptides; 3,952,115, N-acyl-L-methionine ester, N,N'-diacyl-L-cystine ester and N-acyl-L-cysteine ester; 3,959,519, glycylmethionine and methionineglycine; and 4,024,286, dipeptides of methionine with glycine, valine, alanine or glutamic acid.
It has now been found that compounds of formula I below are angiotensin converting enzyme inhibitors and when administered to species of hypertensive mammals they reduce or relieve hypertension particularly of the angiotensin related type. In addition, novel intermediates which are useful in the production of those compounds are potent inhibitors of the carboxypeptidase B-like enzymes and can be used in the treatment of cardiovascular and/or inflammatory conditions.